Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Department of Pediatrics, University of Utah, Salt Lake City, Utah.
Blood Cancer Discov. 2021 May;2(3):266-287. doi: 10.1158/2643-3230.BCD-20-0168. Epub 2019 Dec 2.
We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype-agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML.
我们发现，许多原发性急性髓系白血病（AML）样本和细胞系的存活和生长，但不是正常的 CD34+细胞，依赖于 SIRT5，这是一种赖氨酸去乙酰化酶，涉及调节多种代谢途径。对 SIRT5 的依赖是基因型不可知的，并扩展到 RAS 和 p53 突变的 AML。SIRT5 敲低和使用 NRD167（一种有效的、选择性的 SIRT5 抑制剂）抑制 SIRT5 的结果是可比的。SIRT5 破坏引起的细胞凋亡之前，氧化磷酸化和谷氨酰胺利用减少，线粒体超氧化物增加，而过氧化物歧化酶 2 可减轻这种增加。这些数据表明，SIRT5 控制和协调 AML 中的几个关键代谢途径，并暗示 SIRT5 是 AML 的一个弱点。
